The present invention relates to the use of a series of triazolopyrimidine and pyrazolopyrimidine derivatives as therapeutic agents for the treatment of cachexia, and also provides certain such compounds as novel compositions of matter and provides processes for the preparation of the aforesaid new compounds.
Certain of the triazolopyrimidine compounds used in the present invention are disclosed in Japanese Patent Application Kokai (i.e. as laid open to public inspection prior to examination) No. Sho 51-141896 [Tokko (i.e. as published after examination) No. Sho 57-60356], Japanese Patent Application Kokai No. Sho 52-116497 (Tokko No. Sho 58-437), Japanese Patent Application Kokai No. Sho 53-53697, U.S. Pat. No. 4,007,189 and the Journal of Medicinal Chemistry, 23, 927-937 (1980). In addition certain ketonic compounds of this type were disclosed orally at a meeting of the Pharmaceutical Society of Japan on 28-30 Aug. 1979 and were reported to be of use in the treatment of ischemic heart disease. However, it has not previously been found that any of these known compounds have properties which might render them suitable for the treatment of cachexia.
"Cachexia" is the name given to a generally weakened condition of the body or mind resulting from any debilitating chronic disease. The symptoms include severe weight loss, anorexia and anemia. Cachexia is normally associated with neoplasmic diseases, chronic infectious diseases or thyroiditis, and is a particular problem when associated with cancerous conditions.
Indeed, it has been reported that a large proportion of the deaths resulting from cancer are, in fact, associated with cachexia, as also are various other problems commonly experienced by cancer patients, such as respiratory insufficiency, cardiac failure, diseases of the digestive organs, hemorrhaging and systemic infection [U. Cocchi, Strahlentherapie, 69, 503-520 (1941); K. Utsumi et al., Jap. J. Cancer Clinics, 7, 271-283 (1961)].
Cancer associated cachexia, which decreases the tolerance of cancer patients to chemotherapy and radiotherapy, is said to be one of the obstacles to effective cancer therapy [J. T. Dwyer, Cancer, 43, 2077-2086 (1979); S. S. Donaldson et al., Cancer, 43, 2036-2052 (1979)]. In order to overcome these problems, it used to be common for cancer patients with cachexia to receive a high fat and high sugar diet, or they used to be given high calorie nutrition intravenously. However, it has been reported that symptoms of cachexia were rarely alleviated by these regimens [M. F. Brenann, Cancer Res., 37, 2359-2364 (1977): V. R. Young, Cancer Res., 37, 2336-2347 (1977)].
There are several papers referring to the causes of cachexia. Thus, it has been reported that, in cachexia associated with infection by bacteria or protozoa, certain humoral factors, such as cachectin/TNF (Tumor Necrosis Factor), interleukin I or .gamma.-interferon, may suppress the activity of enzymes such as lipoprotein lipase (E.C.3.1.1.34), which is an essential enzyme for triglyceride metabolism, and acetyl CoA carboxylase and fatty acid synthetase, which are rate determining enzymes in fatty acid synthesis. The same paper also points out that any disorder involving the metabolism of fat may lead the patients to experience severe waste and weight loss [M. Kawakami et al., J. Exp. Med., 154, 631-639 (1981); B. Beutler et al., Nature, 320, 584-588 (1986); B. Beutler et al., J. Immunol., 135, 3969-3971 (1985); R. Kurzrock et al., J. Exp. Med., 164, 1093-1101 (1986); P. H. Pekala et al., Proc. Natl. Acad. Sci. U.S.A., 80, 2743-2747 (1983); S. R. Price et al., Arch. Biochem. Biophys., 251, 738-746 (1986); M. Kawakami, Med. Immunol. 14, 187-190 (1987); J. S. Patton et al., Proc. Natl. Acad. Sci. U.S.A., 83, 8313-8317 (1986)].
On the other hand, it is well known that cancer associated cachexia often results in the depletion of stored body-fat. This depletion is one of the major causes of systemic waste in cancer patients. It has also been suggested that this depletion of body-fat is brought about by increasing the removal of fatty acids from the adipose tissue of cancer patients [A. Theologides, Cancer, 43, 2004-2012 (1979)]. Another paper has reported a correlation between cachexia and a reduction in the activity of plasma lipoprotein lipase [H. Vlassara et al., Horm. Metabol. Res., 18, 698-703 (1986)].
However, on the contrary, there has also been reported an increase in the activity of the plasma lipoprotein lipase in cancer patients suffering from cachexia [H. Masuno et al., Jap. J. Cancer Res., 76, 202-207 (1985)].
Accordingly, the relationship between cachexia and lipoprotein lipase has so far not been definitely established, and there are, indeed, contradictory indications as to whether or not it might be implicated.
We have now discovered that lipoprotein lipase is a key enzyme in cachexia therapy, and that the cachexia in mammals, and hence in humans, may be alleviated by the enhancement of the activity of this enzyme. This enzyme is able to hydrolyze triglyceride in the very low density lipoprotein and the chylomicron to convert the circulating triglyceride to the stored form. We have accordingly provided certain compounds, some of which are new and some of which are known, but all of which have not previously been known to enhance the activity of lipoprotein lipase, and which, by such enhancement, have demonstrated the ability to alleviate the effects of cachexia.